Formulation and Evaluation of Transdermal Patches of Nitrendipine Eudragit RLPO and RSPO Using Rate Controlling Polymers

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RESEARCH ARTICLE
Formulation and Evaluation of Transdermal Patches of Nitrendipine Eudragit
RLPO and RSPO Using Rate Controlling Polymers
Yashoda Chouhan, Sunita Sonartiya, Neelam Patel
Department of Pharmaceutics, Swami Vivekanand College of Pharmacy, Indore, Madhya Pradesh, India
Received: 14 January 2024; Revised: 02 February 2024; Accepted: 05 March 2024
ABSTRACT
This study aims at formulation evaluation of nitrendipine transdermal patch to mitigate hypertension.
In total, six formulations of transdermal patches were prepared, and they were evaluated for various
parameters. The thickness of the patch ranged from 89 ± 2 to 98 ± 6 µm. The folding endurance was
observed to be extended from 178 ± 5 to 225 ± 7. The % moisture content was varied from 5.12 ± 0.22 to
5.69 ± 0.32% while the moisture uptake ranged from 3.12 ± 0.32 to 3.96 ± 0.23%. In addition, the tensile
strength was estimated as 0.45 ± 0.03 to 0.58 ± 0.03 kg/cm2
. The % drug content was found to be maximum
for F2 formulation which is about 99.12 ± 0.23% and lowest in the case of F1 formulation which is about
96.65 ± 0.15%. The in vitro % drug release was noticed to be 99.45 % in F1 and F6 formulations.Although
the % drug release is better for F1 and F6, the F2 formulation is considered to be more superior and ideal
by comparing between above-mentioned parameters.
Keywords: Hypertension, Nitrendipine, transdermal drug delivery system, transdermal patch
INTRODUCTION
The most prevalent modifiable risk factor for death
and disability is hypertension. Other modifiable
risk factors include stroke, heart failure, accelerated
coronary and systemic atherosclerosis, chronic
kidney disease, lowering blood pressure with
antihypertensive medications, reducing the damage
to target organs, and lowering the prevalence of
cardiovascular disease. Typically, hypertension
comes on gradually over time. A person’s risk of
highbloodpressureincreasesiftheyareoverweight,
have a family history of hypertension, do not keep
a healthy diet, or are older than 60. The use of oral
contraceptives, stress, renal illness, diabetes, sleep
apnea, smoking, excessive alcohol consumption,
and a diet high in sodium, low in potassium, and
Vitamin D are among the factors that contribute to
hypertension (Schiffrin, 2001; Chiang et al., 1969).
*Corresponding Author:
Ms. Sunita Sonartiya
E-mail: sunita.sonartiya123@gmail.com
Oneofthefollowingfourgroupsofantihypertensive
medications –ACE inhibitors, angiotensin receptor
blockers (ARBs), calcium channel blockers
(CCBs), and thiazide-type diuretics – may be used
as the first agent. These treatments all lower the
risk of cardiovascular events. A meta-analysis
of 147 randomized controlled trials involving
464,000 hypertensive patients showed that all
major anti-hypertensive drug classes (diuretics,
angiotensin-converting enzyme inhibitors, ARBs,
beta-blockers, and CCBs) cause a reduction in
CAD event and stroke for the reduction in blood
pressure, with the exception of the major effect of
beta blockers administered after MI reduced CAD
event and CCBs reduced stroke. The efficacy and
tolerability of antihypertensive medications should
be taken into consideration while treating adult
hypertension, according to the 2011 ACC/AHA
hypertension guidelines (Arguedas et al., 2009;
Oparil and Schmieder, 2015).
A more modern method of delivering drugs is
called a controlled-release drug delivery system,
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International Journal of Pharmaceutical Biological Archives 2024; 15(1):27-32
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Chouhan, et al.: Formulation and Evaluation of Transdermal Patches of Nitrendipine Eudragit RLPO and RSPO Using Rate
Controlling Polymers
IJPBA/Jan-Mar-2024/Vol 15/Issue 1 28
which releases the medication into the bloodstream
at a predefined pace. These solutions assisted in
overcoming the multidose therapy-related negative
effects of the traditional drug system. For a variety
of reasons, the development of technology that uses
the skin as a port of entry to release drugs into the
systemic circulation at a controlled rate has gained
popularity (Keleb et al., 2010).
Adhesive drug-containing devices with a specific
surface area, known as transdermal drug delivery
systems (TDDS), apply a predetermined dosage of
medication to intact skin at a preprogrammed rate.
Transdermal delivery has grown in significance in
the past few years. Potential benefits of the TDDS
include avoiding hepatic first-pass metabolism,
sustaining stable blood levels for an extended
period of time, which can reduce the need for
frequent doses, enhanced bioavailability, less
gastrointestinal discomfort, and increased patient
compliance (Gaikwad et al., 2013).
Transdermal patch dosage form of transdermal
therapeutic system (TTS) has been commercially
available since the early 1980s. Comparing this
approach to alternative traditional systems, there are
numerous important clinical advantages. As a result,
the TTS has special clinical importance in the long-
term management and prevention of chronic illnesses
such as hypertension. While certain antihypertensive
medications have already been developed and tested
as transdermal patches, the majority are still untested.
In the near future, transdermal formulation of
antihypertensive drugs is a promising development
(Rastogi and Yadav, 2012).
A transdermal patch is an adhesive patch with
medication that is applied topically to transfer a
predetermined amount of medication through the
skin and into the bloodstream. This frequently
encourages the body’s wounded area to mend.
Compared to other methods of medication delivery,
suchasoral,topical,intravenous,andintramuscular,
a transdermal drug delivery route has the advantage
of allowing for controlled medication release into
the patient through the patch. This is typically
achieved by either a porous membrane covering
a reservoir of medication or by body heat melting
thin layers of medication embedded in the adhesive
(Wokovich et al., 2006).
The commonly used drug for hypertension is
nitrendipine. Nitrendipine is a Calcium Channel
Blocker (CCB) with a vasodilator properties. It is
a moderately natriuretic agent instead of sodium
retentive, which sets it apart from other CCBs.
It is also an excellent antihypertensive agent.
Nitrendipine prevents the inflow of extracellular
calcium across the smooth muscle cell membranes
of the heart and blood vessels by rupturing the
channel, blocking ion-control gating mechanisms,
and/or interfering with the release of calcium
from the sarcoplasmic reticulum. Reduction of
intracellular calcium causes myocardial smooth
muscle cell contractile processes to be inhibited,
which dilates coronary and systemic arteries,
increases oxygen delivery to the myocardial tissue,
reduces total peripheral resistance, lowers systemic
blood pressure, and reduces afterload (Santiago
and Lopez, 1990; Scriabine, 1984).[1-10]
MATERIALS AND METHODS
Nitrendipine was obtained as a gift sample from
the pharmaceutical industry. Chemicals such
as Eudragit RLPO and RSPO, chloroform, and
methanol with PEG 600, HPMC, Ethyl Cellulose,
and Glycerin were obtained from Loba Chemie
Pvt. Ltd. Mumbai.
Preparation of Blank Patches
Accurately weighed polymers were taken in
combination and dissolved in respective solvents
(chloroform and methanol in the ratio of 1:1 v/v)
then poured in Petri dish with glycerin on the plain
surface. Then film was dried overnight at room
temperature.
Preparation of Rate Controlling Membrane
Eudragit RLPO and RSPO were used for the
preparation of rate-controlling membranes.
Polymers were dissolved in chloroform and
methanol with PEG 600 as plasticizer (Table 1).
Then, solution was then poured into a glass Petri
dish. The solvent was allowed to evaporate under
room temperature for 24 h (Prajapati et al., 2011).

Preparation of Matrix Type Transdermal
Patches
Transdermal patches are composed of different
polymers HPMC, ethyl cellulose, Eudragit RLPO,
and Eudragit RSPO (Madishetti et al., 2010).
The polymers were dissolved in chloroform and
methanol along with plasticizer (Table 2). Then,
the solution was poured into a glass Petri dish
containing glycerin. The solvent was allowed to
evaporate under room temperature for 24 h. The
polymers (total weight: 500 mg) and drug (20 mg)
were weighed in requisite ratios and dissolved
in 10 mL of chloroform and methanol and PEG
400. After vortexing, the solution was poured on
glycerin placed in a glass Petri dish and dried at
room temperature for 24 h.
Dose Calculations
Width of the plate = 5 cm, length of the
plate = 12 cm, No. of 2.5 × 2.5 cm2
wafers present
whole plate = 12, each wafer contains 10 mg of
drug, 12 no. of wafers contains mg of drug= 20×12
= 240 mg, the amount of drug added in each plate
was approximately equal to 240 mg.
Evaluation Parameters
The prepared transdermal patches were evaluated
for the following parameters (Table 3):
Microscopic Evaluation
An optical microscope (Olympus-Cover-018) with
a camera attachment (Minolta) was used to observe
the shape of the prepared transdermal patch for all
formulations.[11]
Table 2: Evaluation parameters
S.
No.
Formulation
code
Thickness*
(µm)
Folding
Endurance* (times)
% Moisture
content*
% Moisture
uptake*
Tensile strength
(kg/cm2
)
% Drug
content
1 F1 92±5 185±8 5.58±0.15 3.45±0.15 0.45±0.03 96.65±0.15
2 F2 89±2 225±7 5.12±0.22 3.12±0.32 0.48±0.05 99.12±0.23
3 F3 96±3 186±2 5.69±0.32 3.85±0.14 0.52±0.04 97.85±0.22
4 F4 98±6 205±6 5.48±0.15 3.96±0.23 0.58±0.03 96.65±0.18
5 F5 95±5 178±5 5.36±0.16 3.47±0.25 0.49±0.02 98.12±0.16
6 F6 97±4 165±8 5.47±0.22 3.65±0.36 0.52±0.04 97.66±0.15
*Average of three determinations (n=3, mean±S.D.)
Table 1: Preparation of matrix‑type transdermal patches
Formulation
Code
Drug
(mg)
HPMC
(mg)
RLPO
(mg)
RSPO
(mg)
Ethyl
cellulose (mg)
Total polymer
weight (mg)
Plasticizer
% w/w
Permeation
Enhancer % w/w
F1 240 250 150 ‑ 100 500 0.5 10
F2 240 300 100 ‑ 100 500 0.5 10
F3 240 350 50 ‑ 100 500 0.5 10
F4 240 250 ‑ 150 100 500 0.5 10
F5 240 300 ‑ 100 100 500 0.5 10
F6 240 350 ‑ 50 100 500 0.5 10
Plasticizer % w/w of total polymer PEG 6000 (mL). Permeation Enhancer % w/w of total polymer (Methanol, chloroform) mL
Table 3: In vitro % permeation profile of nitrendipine in
formulation F1‑F6
Time
(h)
% of drug release
F1 F2 F3 F4 F5 F6 Pure
drug
0.5 26.65 24.45 22.32 36.65 32.25 30.25 46.65
1 43.32 36.65 30.25 48.85 43.32 42.12 69.98
2 68.85 53.32 45.65 59.98 53.32 50.36 96.65
4 76.65 68.85 55.56 68.85 63.32 60.32 ‑
6 83.32 76.65 63.32 89.98 85.45 83.32 ‑
8 98.12 89.98 74.45 96.65 93.36 90.32 ‑
10 99.12 94.45 88.85 98.85 98.78 98.85 ‑
12 99.45 99.15 93.32 99.12 99.19 99.45 ‑

Thickness
The thickness of the patch was measured by
Vernier calipers. The thickness of patches was
measured at three different places and an average
of three readings was taken with standard deviation
(Tanwar et al., 2007).[12]
Folding Endurance
This was determined by repeatedly folding one film
at the same place until it had broken. The number
of times the film could be folded at the same
place without breaking/cracking gave the value of
folding endurance (Shivaraj et al., 2010).[13]
Tensile Strength
Cut the patch at the center having 2 cm length and
2 cm breadth. Patch was hanged on the top and
lower side of the instrument, then start the switch,
and note the reading on the screen. The thickness
and breadth of strips were noted at three sites and
the average value was taken for calculation. The
tensile strength was calculated by dividing applied
force by cross-sectional area (Alka et al., 2012).[14]
Percentage of Moisture Content
The prepared patches were weighed individually
and kept in desiccators containing activated silica
at room temperature for 24 h (Amish et al., 2012).
Individual patches were weighed. The percentage
of moisture content was calculated as the difference
between the final and initial weight with respect to
the initial weight.[15]
Percentage of Moisture Uptake
First, weighed the patches and then kept in a
desiccator at room temperature for 24 h and then
its exposed to 84% RH (A saturated solution of
potassium chloride) in a desiccator. The % of
moisture uptake was calculated by the difference
between the final and initial weight with respect to
the initial weight (Kriplani et al., 2018).[16]
Drug Content Analysis
The patches (n = 3) of a specified area (6.16 cm2
)
were taken into a 10 mL volumetric flask and
dissolved in methanol (10 mL) with the help
of shaker. After the vortex, the solution was
filtered and prepared subsequent dilutions and
analyzed by UV spectrophotometer at 222 nm
(Teja et al., 2012).[17]
In Vitro Skin Permeation Study
The in vitro skin permeation study was done using
a Franz diffusion cell (receptor compartment
capacity: 80 mL: surface area: 3.14 cm2
. The egg
membrane was separated and used for in vitro
study (Table 4). The receiver compartment was
filled with 40 mL of phosphate buffer, pH = 7.4.
The transdermal patch was firmly pressed onto the
center of the egg membrane and then the membrane
Table 4: In vitro drug release data for optimized formulation F2
Time (h) Square root of
time (h) 1/2
Log time Cumulative*
% drug release
Log cumulative
% drug release
Cumulative
Drug remaining
Log cumulative
% Drug remaining
0.5 0.707 −0.301 24.45 1.388 75.55 1.878
1 1 0 36.65 1.564 63.35 1.802
2 1.414 0.301 53.32 1.727 46.68 1.669
4 2 0.602 68.85 1.838 31.15 1.493
6 2.449 0.778 76.65 1.885 23.35 1.368
8 2.828 0.903 89.98 1.954 10.02 1.001
10 3.162 1 94.45 1.975 5.55 0.744
12 3.464 1.079 99.15 1.996 0.85 −0.071
Table 5: Regression analysis data of nitrendipine
transdermal patches
Batch Zero order First order
r²
F2 0.91 0.921

was mounted on the donor compartment (Vidyavati
and Jithan, 2010). The donor compartment was
then placed in a position such that the surface of the
membrane just touches the receptor fluid surface.
The whole assembly was kept on a magnetic stirrer
with suitable rpm throughout the experiment using
magnetic beads. The temperature of the receptor
compartment was maintained at 37 ± 0.5°C.[18,19]
RESULTS AND DISCUSSION
In total, six formulations of transdermal patches
were prepared and they were evaluated for various
parameters. The thickness of the patch ranged
from 89 ± 2 to 98 ± 6 µm. The folding endurance
was observed to be extended from 178 ± 5 to
225 ± 7. The concentration of polymers also affects
folding durability, which can result in outstanding
fold qualities. The purpose of plasticizers in
transdermal patches is to enhance the film’s look
and film-forming capabilities. The PEG 6000
in patches provides more flexibility at higher
plasticizer concentrations. The % moisture content
varied from 5.12 ± 0.22 to 5.69 ± 0.32% while the
moisture uptake ranged from 3.12 ± 0.32 to 3.96 ±
0.23%.
Studies on the moisture content and moisture
uptake of the patches showed a direct relationship
between the concentration of hydrophilic polymer
and the patches’ increased moisture content and
moisture uptake. The produced formulations had a
low moisture content, which may have contributed
to their stability and decreased brittleness after
extended storage. In addition, the formulations’low
moisture uptake may have reduced their bulkiness
and shielded them from microbial contamination.
In addition, the tensile strength was estimated
as 0.45 ± 0.03 to 0.58 ± 0.03 kg/cm2
. The %
drug content was found to be maximum for F2
formulation which is about 99.12 ± 0.23% and
lowest in the case of F1 formulation which is about
96.65 ± 0.15%. The in vitro % drug release was
noticed to be 99.45% in F1 and F6 formulations
(Figure 1). Although the % drug release is better
for F1 and F6, the F2 formulation is considered to
be more superior and ideal by comparing between
above-mentioned parameters.
The findings showed that as HPMC concentration
rises, so does the medication release from the
patches. In a 12-h period, the total percentage
of drug release was recorded. It was discovered
that when the hydrophilic polymer concentration
in the polymer matrix increased, so did the drug
release. This is because the creation of gelatinous
holes is caused by the dissolution of a water-
soluble component of the polymer matrix. When
such pores are formulated, the mean diffusion path
length of the drug molecules that are released into
the diffusion medium decreases, increasing the
release rate.
Further, the regression analysis of nitrendipine
transdermal patches was carried out. Mainly the
zero-order and first-order kinetics were in focus
(Table 5). The zero-order kinetic model is a
mathematical representation used to analyze drug
release kinetics. It is characterized by a linear
relationship between time and drug release, with a
constant release rate. In this analysis, Batch F2 has
an r² value of 0.910 for the zero-order model. The
first-order kinetic model is another mathematical
model used to describe drug release kinetics.
It assumes that the drug release rate is directly
proportional to the amount of drug remaining to
be released. Batch F2 has an r² value of 0.921 for
the first-order model. Thus, it can be clearly seen
that the transdermal patch follows the first-order
release kinetics.
CONCLUSION
The preparation technique for the transdermal
nitrendipine patches used in this study is
Figure 1: Percentage of drug release of nitrendipine
transdermal patches

straightforward. Excellent physicochemical
qualities were also demonstrated by every
formulation in terms of thickness, weight
fluctuation, drug content, flatness, folding
durability, moisture content, and moisture uptake.
Still, the F2 formulation was considered as best.
The in vitro release results demonstrated that
the kinds and concentrations of polymers had
an impact on the drug release from the patch
formulation. Drug penetration in vitro has been
examined in relation to the impact of penetration
enhancers such as methanol and chloroform. These
investigations showed that medication permeability
increased with penetration enhancer concentration.
The results of this study showed that putting
nitrendipine topically in the form of a transdermal
patch can alleviate the issues associated with its
oral administration, such as limited absorption due
to dissolution rate and gastrointestinal side effects
so quite helpful in the treatment of patients with
hypertension.
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